Concomitant duplications of opioid peptide and receptor genes before the origin of jawed vertebrates

Abstract

Background: The opioid system is involved in reward and pain mechanisms and consists in mammals of four receptors and several peptides. The peptides are derived from four prepropeptide genes, PENK, PDYN, PNOC and POMC, encoding enkephalins, dynorphins, orphanin/nociceptin and beta-endorphin, respectively. Previously we have described how two rounds of genome doubling (2R) before the origin of jawed vertebrates formed the receptor family.

Methodology/principal findings: Opioid peptide gene family members were investigated using a combination of sequence-based phylogeny and chromosomal locations of the peptide genes in various vertebrates. Several adjacent gene families were investigated similarly. The results show that the ancestral peptide gene gave rise to two additional copies in the genome doublings. The fourth member was generated by a local gene duplication, as the genes encoding POMC and PNOC are located on the same chromosome in the chicken genome and all three teleost genomes that we have studied. A translocation has disrupted this synteny in mammals. The PDYN gene seems to have been lost in chicken, but not in zebra finch. Duplicates of some peptide genes have arisen in the teleost fishes. Within the prepropeptide precursors, peptides have been lost or gained in different lineages.

Conclusions/significance: The ancestral peptide and receptor genes were located on the same chromosome and were thus duplicated concomitantly. However, subsequently genetic linkage has been lost. In conclusion, the system of opioid peptides and receptors was largely formed by the genome doublings that took place early in vertebrate evolution.

Figure 1. Neighbor-Joining tree for the opioid prepropeptide family.

Bootstrap values are shown at the nodes. Abbreviations: PENK preproenkephalin, PDYN preprodynorphin, PNOC preproorphanin and POMC proopioimelanocortin.

Figure 2. Alignment of the preproenkephalin protein sequences.

Conserved cysteines in the N-terminal region are marked with an asterisk and regions corresponding to known mature peptides in either of the sequences are boxed. Enkephalin motifs (YGGFM/L) are shaded.

Figure 3. Alignment of the preprodynorphin protein sequences.

Conserved cysteines in the N-terminal region are marked with an asterisk and regions corresponding to known mature peptides in either of the sequences are boxed. Dynorphin-like motifs (YGGF…) are shaded.

Figure 4. Alignment of the preproorphanin protein sequences.

Conserved cysteines in the N-terminal region are marked with an asterisk and regions corresponding to known mature peptides in either of the sequences are boxed. Orphanin/nociceptin-like motifs (XGGF…) are shaded.

Figure 5. Alignment of the proopioimelanocortin protein sequences.

Conserved cysteines in the N-terminal region are marked with an asterisk and regions corresponding to known mature peptides in either of the sequences are boxed. Enkephalin motifs (YGGFM) are shaded.

Figure 6. Paralogus regions in chicken and human harbouring the opioid peptides and receptors.

Paralogus regions in chicken and human harbouring the opioid peptides and receptors together with several other gene families. For full gene family names see Table S1. Note that several translocations have occurred in human as compared to chicken. Abbreviations: PENK preproenkephalin, PDYN preprodynorphin, PNOC preproorphanin, POMC proopioimelanocortin, OPRM opioid mu receptor, OPRD opioid delta receptor, OPRK opioid kappa receptor and OPRL orphanin receptor.

Figure 7. Proposed evolutionary history and the present locations for the opioid peptide and receptor genes.

A: Proposed evolutionary history for the opioid peptides and receptors by genome and local duplications. The timing of the duplication that generated PNOC and POMC from their common ancestor is still unresolved and three different scenarios are presented. B: The present locations of the opioid peptide and receptor genes in human, chicken and zebrafish. Several gene families in these chromosomal regions have a similar evolutionary history, see Fig. 6 and Table S2. Abbreviations: PENK preproenkephalin, PDYN preprodynorphin, PNOC preproorphanin and POMC proopioimelanocortin, OPRM opioid mu receptor, OPRD opioid delta receptor, OPRK opioid kappa receptor and OPRL orphanin receptor.